The invention is particularly, but not exclusively, applicable to apparatus the sensors of which include piezo-electric and acoustic transducers, for example quartz crystal resonators.
Typically, each acoustic transducer has an active surface which is oscillated, and on which a receptor group is immobilised. The receptor group has chemical affinity or reactivity towards a substance to be detected or analysed. The substance to be analysed is normally suspended in a fluid which is brought into contact with the active surface. Physical, chemical and biochemical interactions between the receptor group on the surface and the substance cause a measurable change in mass attached to the surface and in other physical properties of the active surface, and these can be analysed to obtain qualitative and/or quantitative data on the substance.
Multiplexed assays using multiple sensing elements have found extremely broad utility in drug discovery, life sciences and diagnosis and academic research. The ability to carry out a number of measurements in parallel, or in rapid succession, enables a wide variety of ligand-target interactions to be screened. In addition multiple controls, or redundant positives can be included in an array, increasing the accuracy and reliability of the assay. Both high-density sensor arrays for high-throughput screening applications and lower-density arrays of sensors for various diagnostic applications have been employed to profile oligonucleotide expression levels and genetic mutation (i.e. DNA, cDNA, siRNA, miRNA and PNA chips) and to probe protein expression levels. This has allowed the diagnosis of genetic diseases, the genetic pre-disposition to various non-inherited diseases and both pre- and post-symptomatic diagnosis of diseases due to elevated or depressed levels of key protein biomarkers.
Due to the inherent complexity of biological systems, many diagnostic approaches now require a number of markers, or genetic sequences to be analysed. In drug discovery, many pharmaceutical companies have generated compound libraries with 100,000's to millions of compounds that need to be screened against a number of target receptors in an arrayed format. Arrayed sensor technologies are also being applied to new areas of proteomic and cellular analysis.
Such applications of sensor technology have generated the need to make measurements of different analytes on multiple identical receptors, where each sensor in the array may be brought into contact with a respective fluid sample. Alternatively, a single fluid sample may be conveyed to all of the sensors, each of which carries either a different respective receptor or group of receptors so that multiple tests are performed on the same sample. Applications of multiple analytes on multiple receptors are also known. An efficient means to achieve such types of measurements is to arrange the sensors in an array.
Each transducer may be connected, in turn, to a driver for oscillating the active surface. Signals from the sensor are received and processed at a receiver. The driver and receiver may, with the sensor, form part of an oscillator circuit with positive feedback so that the sensor is made to oscillate at the resonant frequency of that circuit, which frequency would be related to the mechanical resonant frequency of the sensor. Alternatively, the driver and receiver may form part of a network analyser which oscillates the active surface at a frequency which is swept through a range that includes the resonant frequency, and which analyses the frequency dependent admittance of the sensor over that range.
At least the latter type of apparatus, however, can suffer from a lack of high frequency stability and high system noise over practically useful timescales. One reason for the variability of the accuracy of the apparatus is the sensitivity to environmental and in particular thermal effects of the complete transducer-instrument system. Use of special cuts of transducer material such as AT-cut quartz and the use of reference transducers can minimise temperature dependence of the resonators, but this does not overcome the effect of the influence of temperature on the whole system and in particular on the interface between the instrument and the transducer. One particular effect that the applicants have found to limit the commercial development of robust systems using these technologies arises from the temperature dependence of parasitic losses. These arise from stray capacitance between active lines and ground, and distort the measurements made. As the operating frequency increases, the parasitic losses and their temperature dependence become more problematic, and cause drifts in the response of the system having characteristic timescales of 1-1000 seconds. As this is typically the timescale over which measurements are desired to be made, this has impeded development of this type of analytical apparatus.
Accuracy can be improved by monolithic integration of the sensor and interface electronics since this reduces the length of the various tracks, and hence parasitic loss effects. However, the production of such devices requires expensive capital equipment and may not always be practical, particularly as it is not straightforward to integrate discrete quartz/metal sensors into semiconductor device structures. This does not however solve the problem of changes in the variation of loss characteristics with temperature.